Project 3- Summary ?LRRK2 mediated macrophage responses in PD? Post-mortem studies show that brains susceptible to Parkinson disease (PD) develop ?- synuclein inclusions in vulnerable neurons together with immune cell activation. Peripheral immune cells are recruited to the most vulnerable brain regions such as the substantia nigra pars compacta. Historically the interpretation of immune cell activation in the PD brain and pathogenesis has been difficult to understand. However, recent genetic and transcriptomic profiling studies using new sequence databases and gene ontology compendia show that immune cell function may underlie much of the heritable aspects of PD susceptibility. These recent studies highlight a gene known as leucine-rich repeat kinase 2 in driving some of the connection between immune function and PD susceptibility. Rare genetic variants in LRRK2 are among the most common known genetic causes of PD. In the P20 Exploratory center, we found that LRRK2 protein is highly expressed in peripheral macrophages that are recruited nearby neurons in the brain that harbor ?-synuclein inclusions. Studies with global LRRK2-transgenic and knockout mice and rats suggest that LRRK2 may control damaging pro-inflammatory responses in the brain through function in these macrophages. As part of the proposed Alabama Udall Center to study ?Innate and Adaptive Immunity in Parkinson Disease,? we will define peripheral macrophage responses driven by LRRK2 in ?-synuclein induced neurodegeneration. Using genetic, pharmacological, and transplantation approaches, we will restrict LRRK2 activation and inhibition to the periphery and in bone-marrow derived immune cells in rat models of ?-synuclein induced neurodegeneration. In parallel, we will study LRRK2 function in macrophages isolated from patient blood to determine whether LRRK2 mutations exacerbate pro- inflammatory responses in PD susceptibility. Further, we will examine whether macrophage responses from de novo PD patients with elevated LRRK2 expression show elevated pro- inflammatory responses and whether these can be rescued with LRRK2 kinase inhibitors and RNAi approaches. With this work, we hope to gain a better understanding of LRRK2 function in macrophages in neurodegeneration and proof-of-principle therapeutic approaches that might be explored for neuroprotection in LRRK2-linked PD.